Increasing information points to potentiation of Human Immunodeficiency Virus (HIV) replication by herpesviruses. The virus most commonly isolated from AIDS patients is the human cytomegalovirus (HCMV). Although HCMV is ubiquitous in normal populations, it is particularly prevalent in populations at high risk for AIDS, such as homosexual men and intravenous drug abusers. Thus HCMV could potentially serve as an enhancer of HIV infection, converting an asymptomatic latent infection to an active state. This could happen by direct effect of HCMV infection in cells containing HIV, and/or an direct effect of HCMV on the host immune system. In this project, we propose to study the effect of HCMV on HIV replication in vitro and in vivo. HIV infected cells will be coinfected with HCMV or transfected with plasmids containing genome segments. The HCMV gene giving maximum transactivation of HIV will be localized. An mRNA and corresponding transactivating protein will then be sought with HCMV antibodies, by Northern blot analysis and by identification of cDNA in a HCMV cDNA library, followed by in vitro translation. Putative transactivating proteins or HCMV regulatory sequences will be tested for their ability to bind to HIV-LTR or to cellular DNA. The effect of HCMV infection on non-specific immune mechanisms against HIV will also be studied. Natural killer (NK) cell cytotoxicity against HIV-infected T cell lines and fresh T cells will be characterized with respect to effector cells, kinetics, and requirements for interferon-alpha producing HLA-DR+ accessory cells. The effects of low and high passage CMV strains on the ability on NK cells to lyse HIV-infected targets will be determined. In other experiments NK cells exposed to HIV, or to HIV and CMV, will be tested for lytic activity against K562 and CMV-infected targets. Possible mechanisms for reduced lysis by virus-exposed NK cells will be investigated.